Of 93 patients treated with pembrolizumab (Keytruda), 14 developed thyroid dysfunction, for a 15% adverse event rate, shortly after treatment was initiated, said Danae Delivanis, MD, of the Mayo Clinic, Rochester, Minn., and colleagues. Nearly all patients who developed thyroid disorders also received ipilimumab (Yervoy).

Specifically, seven patients developed thyroiditis and seven developed hypothyroidism, including three cases of recurrent disease. Cases were diagnosed from April 2014 to January 2015, she said during a presentation at the International Thyroid Congress.

"We found that combination immune checkpoint blockade enhances the incidence of thyroiditis/hypothyroidism from 6% with ipilimumab alone to 15% when ipilimumab is followed by pembrolizumab," she said.

While Delivanis acknowledged that drugs such as pembrolizumab, ipilimumab, and nivolumab (Opdivo) have revolutionized the treatment of patients with metastatic melanoma, "they are related to multiple immune-related adverse events, many of which target the thyroid gland. Unfortunately these events have been poorly recognized."

For this retrospective study, they identified all patients with metastatic melanoma who received pembrolizumab and, in some case, ipilimumab. They also included a few patients who were receiving pembrolizumab in controlled clinical trials of other solid tumors such as non-small cell lung cancer (NSCLC).

The median patient age was 58. Of those who were diagnosed with thyroid-related events, 13 were being treated for melanoma; the other for NSCLC. The median time to thyroid dysfunction was 6 weeks.

Levels of anti-thyroid peroxidase antibodies (anti-TPO), which were available in 10 cases, were elevated in no cases of thyroiditis, in two cases of new onset hypothyroidism, and in three cases of recurrent hypothyroidism.

On PET/CT studies, new thyroid FDG uptake was seen in six cases with no correlation to anti-TPO status, the authors reported.

They pointed out that only 50% of patients developed elevated anti-TPO antibodies, suggesting autoantibody dependent and independent mechanisms.

"Ongoing studies are underway to better understand its pathophysiology in order to improve clinical care," they wrote.

However, the findings from this research could justify using immune checkpoint blockade to "induce anti-thyroid responses in patients with therapeutically refractory metastatic differentiated thyroid cancer," they noted.

In commenting on the study, Maria Cabanillas, MD, associate professor in endocrine neoplasia and hormone disorders at the University of Texas MD Anderson Cancer Center, told MedPage Today, that the immunotherapy agents work by "ramping up the immune system," so a side effect of that attack on cancer could be an increased risk of autoimmune disorders.

"These are early complications that are being seen with the checkpoint inhibitors," Cabanillas said. "The median time to the thyroiditis was two cycles and the cycles are typically every 3 weeks, so this is happening pretty early on."

She said that the same phenomenon is seen in patients who develop inflammation of the pituitary gland. "It happens very early, around the second or third cycle. These drugs release the brakes on the immune system, and by releasing those brakes, of course, you can get autoimmune diseases. It can cause problems with the colon; it can be the liver; it can be the thyroid."

Cabanillas said that the Mayo researchers are reporting on thyroiditis with pembrolizumab "which is usually what we see with this class of checkpoint inhibitors but there are other types of checkpoint inhibitors, such as ipilimumab, [that]...cause more pituitary adverse events."

She said the treatment with pembrolizumab causes a transient thyroiditis which is followed by thyroid failure. "The thyroid gland is being destroyed and it is releasing thyroid hormone, but once those cells are destroyed, the patients become hypothyroid very precipitously," she said.

Cabanillas noted that when a patient develops hypothyroidism, they exhibit extreme fatigue, as do cancer patients undergoing treatment, so it may be difficult to realize there is a thyroid problem with these patients.

"We have to follow these patients closely with thyroid function tests," Cabanillas said, noting that part of the package insert for pembrolizumab is the suggestion to perform regular thyroid function testing. The prescription information suggests that thyroid function should be assessed at baseline and throughout the treatment, but Cabanillas advocated for monthly thyroid function tests.

Delivanis and co-authors disclosed no relevant relationships with industry.

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